1 Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM) , Madrid, Spain .
2 Center for Biomedical Research on Rare Diseases (Ciberer), Unit 708, Instituto de Salud Carlos III , Madrid, Spain .
Thyroid. 2018 Sep;28(9):1211-1220. doi: 10.1089/thy.2018.0008. Epub 2018 Jun 29.
Loss of function mutations in the thyroid hormone (TH)-specific cell membrane transporter, the monocarboxylate transporter 8 (MCT8), lead to profound psychomotor retardation and abnormal TH serum levels, with low thyroxine (T4) and high triiodothyronine (T3). Several studies point to impaired TH transport across brain barriers as a crucial pathophysiological mechanism resulting in cerebral hypothyroidism. Treatment options for MCT8-deficient patients are limited and are focused on overcoming the brain barriers. The aim of this study was to evaluate the ability of the TH analog sobetirome and its prodrug Sob-AM2 to access the brain and exert thyromimetic actions in the absence of Mct8.
Juvenile wild-type (Wt) mice and mice lacking Mct8 and deiodinase type 2 (Mct8/Dio2KO) were treated systemically with daily injections of vehicle, 1 mg of sobetirome/kg body weight/day, or 0.3 mg of Sob-AM2/kg body weight/day for seven days. Sobetirome content was measured using liquid chromatography-tandem mass spectrometry, and T4 and T3 levels by specific radioimmunoassays. The effect of sobetirome treatment in the expression of T3-dependent genes was measured in the heart, liver, and cerebral cortex by real-time polymerase chain reaction.
Sob-AM2 treatment in Mct8/Dio2KO animals led to 1.8-fold more sobetirome content in the brain and 2.5-fold less in plasma in comparison to the treatment with the parent drug sobetirome. Both sobetirome and Sob-AM2 treatments in Mct8/Dio2KO mice greatly decreased plasma T4 and T3 levels. Dio1 and Ucp2 gene expression was altered in the liver of Mct8/Dio2KO mice and was not affected by the treatments. In the heart, Hcn2 but not Atp2a2 expression was increased after treatment with the analogs. Interestingly, both sobetirome and Sob-AM2 treatments increased the expression of several T3-dependent genes in the brain such as Hr, Abcd2, Mme, and Flywch2 in Mct8/Dio2KO mice.
Sobetirome and its amide prodrug Sob-AM2 can access the brain in the absence of Mct8 and exert thyromimetic actions modulating the expression of T3-dependent genes. At the peripheral level, the administration of these TH analogs results in the depletion of circulating T4 and T3. Therefore, sobetirome and Sob-AM2 have the potential to address the cerebral hypothyroidism and the peripheral hyperthyroidism characteristic of MCT8 deficiency.
甲状腺激素（TH）特异性细胞膜转运蛋白单羧酸转运蛋白 8（MCT8）的功能丧失突变导致明显的精神运动发育迟缓以及异常的 TH 血清水平，即低甲状腺素（T4）和高三碘甲状腺原氨酸（T3）。几项研究指出，脑内 TH 转运障碍是导致脑甲状腺功能减退的关键病理生理机制。MCT8 缺陷患者的治疗选择有限，主要集中在克服血脑屏障障碍。本研究旨在评估 TH 类似物索比替罗及其前体药物 Sob-AM2 在缺乏 Mct8 的情况下进入大脑并发挥甲状腺素作用的能力。
使用每日注射 vehicle、1mg/kg 体重/天的索比替罗或 0.3mg/kg 体重/天的 Sob-AM2，对幼年野生型（Wt）小鼠和缺乏 Mct8 和脱碘酶 2（Mct8/Dio2KO）的小鼠进行全身治疗，持续 7 天。使用液相色谱-串联质谱法测量索比替罗的含量，并使用特异性放射免疫分析法测量 T4 和 T3 的水平。通过实时聚合酶链反应测量索比替罗治疗对心脏、肝脏和大脑皮层中 T3 依赖性基因表达的影响。
与母体药物索比替罗治疗相比，Sob-AM2 治疗 Mct8/Dio2KO 动物可使大脑中的索比替罗含量增加 1.8 倍，血浆中的含量减少 2.5 倍。索比替罗和 Sob-AM2 治疗均可显著降低 Mct8/Dio2KO 小鼠的血浆 T4 和 T3 水平。Mct8/Dio2KO 小鼠肝脏中的 Dio1 和 Ucp2 基因表达发生改变，但治疗并未影响其表达。有趣的是，在心脏中，Hcn2 而非 Atp2a2 的表达在类似物治疗后增加。有趣的是，索比替罗和 Sob-AM2 治疗均可增加 Mct8/Dio2KO 小鼠大脑中多个 T3 依赖性基因的表达，如 Hr、Abcd2、Mme 和 Flywch2。
在缺乏 Mct8 的情况下，索比替罗及其酰胺前体药物 Sob-AM2 可进入大脑并发挥甲状腺素作用，调节 T3 依赖性基因的表达。在外周水平，这些 TH 类似物的给药会导致循环 T4 和 T3 的耗竭。因此，索比替罗和 Sob-AM2 有可能解决 MCT8 缺乏症的脑甲状腺功能减退症和外周甲状腺功能亢进症。
